Ovarian cancer ranks fifth among malignancies affecting women in the United States. The onset of ovarian cancer is insidious and the symptoms are nonspecific, such that two-thirds of women present with advanced disease at diagnosis. Although the initial response rate of patients with advanced disease after treatment with platinum and taxol is 73% to 77%, a large majority develop recurrent disease. These factors contribute to ovarian cancer having the highest mortality rate of all gynecologic tumors. Thus, alternative methods for treatment are a priority for ovarian cancer.
The identification of ovarian tumor-specific antigens that can serve as targets for CD8+ cytotoxic T lymphocytes (CTLs) (9) and the harnessing of dendritic cells that possess the ability to induce CTL responses to those targets (11, 12) suggests that dendritic cell immunotherapy may be of potential therapeutic benefit. Monocyte-derived dendritic cells loaded with tumor lysate antigen can induce tumor-specific CTL lysis of autologous tumor cells from patients with ovarian cancer or uterine serous papillary carcinoma (13, 14), and dendritic cells pulsed with peptides acid-eluted from HLA class I on the surface of ovarian tumor cells can stimulate CTL killing of autologous tumor (16).
The identification of appropriate tumor-specific antigens is a critical component for the development of successful ovarian tumor-specific immunotherapy.
Tumor-associated serine proteases are involved in many biological functions of cancer cells, including activation of growth and angiogenic factors and promotion of invasion and metastasis. Among the serine proteases overexpressed in some cancers is stratum corneum chymotryptic enzyme. Stratum corneum chymotryptic enzyme (SCCE), also known as kallikrein 7, is a serine protease that is overexpressed by ovarian cancer cells but not expressed by normal ovaries or other normal adult tissues, except the outermost cornified layer of the skin (15). Immunohistochemical analysis of 14 ovarian tumors showed positive staining localized to the cytoplasm and cell membrane, suggesting that SCCE may be expressed as both secreted and membrane forms (15). Quantitative RT-PCR revealed SCCE expression in >88% of serous ovarian tumors, 100% of endometrioid and clear cell tumors, but only 29% (two of seven) of mucinous tumors (15). SCCE is also overexpressed in cervical cancer (10).
Hepsin is a transmembrane serine protease that is overexpressed in prostate cancer and ovarian cancer, as well as renal cell carcinoma (19-26). In at least one report its overexpression was linked to metastasis and tumor progression (21).
Matriptase (also known as TADG-15) is a transmembrane serine protease that was discovered in 1993 and cloned in 1999 (3, 7). It is overexpressed in many tumors of epithelial origin, including carcinomas of the head and neck, mesothelium, breast, ovary, cervix, prostate, lung, and gastrointestinal tract, as well as in cell lines derived from these tumors (8). Its expression has been linked to increased tumor invasiveness (5-6). It is expressed in a high percentage of ovarian carcinomas but not in normal ovary tissue (4).
New treatments for ovarian and other cancers are needed. New targets for cancer immunotherapy are needed.